What is the role of Angiotensin Receptor-Neprilysin Inhibitor (ARNI)?

From the Guidelines

Angiotensin receptor-neprilysin inhibitors (ARNIs) should be used to treat heart failure with reduced ejection fraction (HFrEF) in patients who tolerate an ACE inhibitor or ARB, as they have been shown to reduce morbidity and mortality compared to ACE inhibitors, as demonstrated in the PARADIGM-HF trial 1.

Key Points

• ARNIs, such as sacubitril/valsartan (Entresto), combine a neprilysin inhibitor with an angiotensin receptor blocker to reduce cardiac workload, promote vasodilation, and decrease fluid retention.
• The typical starting dose of sacubitril/valsartan is 24/26 mg twice daily, which can be titrated up to 97/103 mg twice daily as tolerated.
• ARNIs have been shown to reduce hospitalization and mortality in heart failure patients compared to ACE inhibitors, with a 20% relative reduction in the composite endpoint of cardiovascular death or HF hospitalization in the PARADIGM-HF trial 1.
• Common side effects of ARNIs include hypotension, hyperkalemia, dizziness, and renal dysfunction.
• ARNIs should not be used concurrently with ACE inhibitors (require a 36-hour washout period) and are contraindicated in pregnancy and in patients with a history of angioedema, as noted in the 2017 ACC/AHA/HFSA focused update 1.

Clinical Use

• Patients with chronic stable HFrEF who tolerate ACEi and ARB should be switched to ARNi, as recommended in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1.
• ARNi should be initiated de novo in patients hospitalized with acute HFrEF before discharge in the absence of contraindications, and may be initiated de novo in patients with chronic symptomatic HFrEF to simplify management, as suggested in the 2022 AHA/ACC/HFSA guideline 1.

Monitoring

• Regular monitoring of blood pressure, renal function, and potassium levels is essential during treatment with ARNIs, as recommended in the 2022 AHA/ACC/HFSA guideline 1.

From the Research

Angiotensin Receptor-Neprilysin Inhibitor Overview

• Angiotensin receptor-neprilysin inhibitors (ARNIs) are a class of drugs used to treat heart failure with reduced ejection fraction (HFrEF) 2, 3.
• ARNIs work by blocking the action of angiotensin II, a potent vasoconstrictor, and inhibiting the breakdown of neprilysin, a peptide that counteracts the effects of angiotensin II 3.
• The use of ARNIs has been shown to reduce mortality and hospitalization rates in patients with HFrEF, and is considered a foundational therapy for this condition 2, 3, 4.

Clinical Evidence

• Studies have demonstrated the efficacy of ARNIs in improving clinical outcomes in patients with HFrEF, including reduced risk of all-cause mortality, cardiac death, and major adverse cardiac events (MACEs) 3, 5, 4.
• A network meta-analysis comparing ARNIs, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACE-Is) found that ARNIs were associated with improved clinical outcomes, except for a higher risk of hypotension 4.
• Another study found that the initiation or optimization of ARNIs during hospitalization for acute decompensation was feasible and well-tolerated, and led to improvements in clinical parameters and functional status 6.

Treatment Guidelines

• Current guidelines recommend the use of ARNIs as a foundational therapy for patients with HFrEF, unless there are specific contraindications 2, 3.
• The guidelines also recommend the use of other disease-modifying therapies, such as beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors, in combination with ARNIs 2, 6.
• The choice of therapy should be individualized based on patient characteristics, comorbidities, and preferences 3, 6.